The hyperthermia induced by sympathomimetic agents such as Ecstasy (3,4- methylenedioxymethamphetamine, MDMA) is the most acute life-threatening consequence associated with their use. With the ever-increasing popularity of Ecstasy among today's youth, the elucidation of the mechanisms by which this hyperthermia occurs is crucial to developing optimal treatments. The overall HYPOTHESIS to be evaluated is that temporal increases in plasma free fatty acids (FFAs), norepinephrine (NE) and epinephrine (Epi) contribute to the activation of skeletal muscle uncoupling protein 3 (UCP3) and produce a thermogenic crisis following exposure to Ecstasy. Specific Aims: (1) Characterize plasma changes in FFAs, NE and Epi during the heat generation phase (0 to 60 minutes post-treatment) of Ecstasy exposure. These changes in plasma levels will then be correlated to the thermogenic effects of Ecstasy. (2) Define the intracellular transduction mechanisms which mediate UCP3-dependent hyperthermia as a consequence of Ecstasy use. These studies will be performed in both in vivo and in vitro models in order to obtain a thorough understanding of the cellular mechanisms involved in Ecstasy-induced thermogenesis. Significance. These studies will provide insight into the cellular mechanisms vital to the hyperthermia initiated by both Ecstasy and other sympathomimetic agents. Furthermore, defining the mechanisms of UCP3 activation will lead to improved targeted therapies for treatment of heat-related illnesses such as pheochromocytoma and hyperthyroidism. Over the past decade, the number of emergency room visits associated with stimulant abuse such as Ecstasy and methamphetamine has dramatically increased. One of the most acute life-threatening consequences of these agents is hyperthermia. This proposal will examine the factors that contribute to the development of this hyperthermia. The research proposed in this application is significant, because understanding the mechanism underlying Ecstasy-induced hyperthermia will provide a basis for the development of treatments for hyperthermia not only from Ecstasy and other sympatho- mimetic agents (methamphetamine) but also for other heat-related illnesses (eg. thyrotoxic [unreadable] crisis). [unreadable] [unreadable] [unreadable]